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Tissue-type Plasminogen Activator Regulates Macrophage Activation and Innate Immunity

Elisabetta Mantuano, Pardis Azmoon, Coralie Brifault, Michael A. Banki, Andrew S. Gilder, Wendy M. Campana and Steven L. Gonias

Key points

  • Tissue-type plasminogen activator inhibits the activity of the innate immune system in macrophages in vitro and in vivo in mice.

  • Suppression of macrophage pro-inflammatory responses by tPA requires the NMDA Receptor.

Abstract

Tissue-type plasminogen activator (tPA) is the major intravascular activator of fibrinolysis and a ligand for receptors involved in cell-signaling. In cultured macrophages, tPA inhibits the response to lipopolysaccharide (LPS) by a pathway that apparently requires LDL Receptor-related Protein-1 (LRP1). Herein, we show that the mechanism by which tPA neutralizes LPS involves rapid reversal of IκBα phosphorylation. tPA independently induced transient IκBα phosphorylation and ERK1/2 activation in macrophages; however, these events that did not trigger inflammatory mediator expression. The tPA signaling response was distinguished from the signature of signaling events elicited by pro-inflammatory LRP1 ligands, such as Receptor-associated Protein (RAP), which included sustained IκBα phosphorylation and activation of all three MAP kinases (ERK1/2, c-Jun kinase, and p38 MAP kinase). Enzymatically-active and inactive tPA demonstrated similar immune modulatory activity. Intravascular administration of enzymatically-inactive tPA in mice blocked the toxicity of LPS. In mice not treated with exogenous tPA, the plasma concentration of endogenous tPA increased 3-fold in response to LPS, to 116±15 pM, but remained below the approximate threshold for eliciting anti-inflammatory cell-signaling in macrophages (~2.0 nM). This threshold is readily achieved in patients when tPA is administered therapeutically for stroke. In addition to LRP1, we demonstrate that the N-Methyl-d-Aspartic acid Receptor (NMDA-R) is expressed by macrophages and essential for anti-inflammatory cell-signaling and regulation of cytokine expression by tPA. The NMDA-R and Toll-like Receptor-4 were not required for pro-inflammatory RAP-signaling. By mediating the tPA response in macrophages, the NMDA-R provides a pathway by which the fibrinolysis system may regulate innate immunity.

  • Submitted April 18, 2017.
  • Accepted July 3, 2017.